Gene-environment interactions in the etiology, symptomatology and treatment of Posttraumatic Stress Disorder
Biological Psychiatry
Final Report Abstract
The aim of the project Gene-environment-interactions in the etiology, symptomatology and therapy of posttraumatic stress disorder (PTSD) was to identify novel genetic markers contributing to the risk to develop PTSD and influencing the response to exposure-based treatment. Since the probability to develop PTSD depends on the genetic makeup of a person and the amount of traumatic events experienced (trauma load), it is crucial to adequately access trauma load and to include this environmental risk factor in gene × environment interaction studies. Therefore, we conducted two studies, which investigated how trauma load can be best assessed and quantified. Our results indicated that the simple sum score of traumatic event types experienced is a valid and economic measure for trauma load, as considering the frequency as well as the weighting of events did not substantially improve the prediction of PTSD risk. Furthermore, we were able to show that trauma load does not only influence PTSD risk, but also the modification of trauma memories by exposure-based therapy. Consequently, the sum score of the number of different traumatic event types experienced was included in all genetic analyses. As a next step, we conducted a GWAS, which tested for the association of hundreds of thousands of genetic markers at once in a sample of 924 survivors of the war of the rebel group Lord’s Resistance Army (LRA) in Northern Uganda while simultaneously considering the effect of traumatic load and potential gene × environment interactions. We identified SNP rs3852144, an intronic marker on chromosome 5, to be associated with lifetime PTSD risk. Results could be replicated in an independent sample of Rwandan genocide survivors. This SNP was furthermore associated with memory-performance in healthy individuals and treatment response in PTSD diagnosed individuals treated with Narrative Exposure Therapy (NET). Findings clearly show the potential to combine PTSD and memory research. Furthermore, we conducted the first study testing for associations of gene FKBP5, known to affect stress regulation and memory, with treatment success. In a subsample of PTSD diagnosed individuals treated with NET, we found that rs1360780 homozygous C/C-carriers showed continuous symptom improvement following the end of NET, while carriers of the rs1360780 risk (T) allele indicated a symptom relapse 10 months after the end of therapy. This points towards a substantial role of FKBP5 in long-term therapeutic success. Integrating candidate gene and pathway analysis we furthermore identified gene candidate NOTCH, primarily known for its involvement in fear- and memory-processes from animal studies, as a novel mediator for the risk to develop PTSD in humans. Taken together, our project showed how to best quantify trauma load and how this environmental risk factor can be best considered in genetic research on PTSD risk. Moreover, we identified novel, memory-related genetic markers for PTSD risk and treatment success. These identified genes and their molecular pathways might be future targets for pharmacological interventions striving to improve PTSD treatment. Dr. Sarah Wilker, first author of three publications, was awarded with the Young Academics Award of the German-Speaking Society for Psychotraumatology and the dissertation award of the University Society Ulm (Ulmer Universitätsgesellschaft) for her publications based on this D-A-CH funded project.
Publications
- (2018) Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample. Translational psychiatry 8 (1) 251
Wilker, Sarah; Schneider, Anna; Conrad, Daniela; Pfeiffer, Anett; Boeck, Christina; Lingenfelder, Birke; Freytag, Virginie; Vukojevic, Vanja; Vogler, Christian; Milnik, Annette; Papassotiropoulos, Andreas; J-F de Quervain, Dominique; Elbert, Thomas; Kolas
(See online at https://doi.org/10.1038/s41398-018-0297-1) - (2014). The downside of strong emotional memories: How human memory-related genes influence the risk for posttraumatic stress disorder – A selective review. Neurobiology of Learning and Memory, 112
Wilker, S., Elbert, T., & Kolassa I.-T.
(See online at https://doi.org/10.1016/j.nlm.2013.08.015) - (2014). The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder. Translational Psychiatry, 4(6), e403
Wilker, S., Pfeiffer, A., Kolassa, S., Elbert, T., Lingenfelder, B., Ovuga, E., Papassotiropoulos P, de Quervain D. & Kolassa, I. T.
(See online at https://doi.org/10.1038/tp.2014.49) - (2015). How to quantify exposure to traumatic stress? Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population. European Journal of Psychotraumatology, 6(1), 28306
Wilker, S., Pfeiffer, A., Kolassa, S., Koslowski, D., Elbert, T., & Kolassa, I. T.
(See online at https://doi.org/10.3402/ejpt.v6.28306) - (2017). Does trauma event type matter in the assessment of traumatic load? European Journal of Psychotraumatology, 8(1), 1344079
Conrad, D., Wilker, S., Pfeiffer, A., Lingenfelder, B., Ebalu, T., Lanzinger, H., ... & Kolassa, S.
(See online at https://doi.org/10.1080/20008198.2017.1344079)
